Recent case reports suggest that HIV-1 super infection, or sequential infection with different variants of HIV- 1, can occur, even in subtype B epidemics. The circumstances and clinical consequences of super infection are not known. For example, antiviral therapies frequently select drug resistant HIV-1, which can be transmitted to previously uninfected persons, but whether drug resistant HIV-1 can be transmitted to persons already infected with HIV-1 is not known. Further, antiretroviral therapy may increase susceptibility to super infection due to decreased viral interference and decreased anti-viral immunity. If so, widespread use of antiviral therapy in communities could facilitate the spread of HIV-1 variants that are more drug resistant, more virulent, or more transmissible. We propose to expand a prospective pilot study of HIV-1 infected couples that are highly exposed to partners having highly divergent and genetically distinguishable variants of HIV- 1. These couples provide a unique opportunity to determine the frequency, circumstances, and clinical consequences of systemic super infection among persons with well-characterized exposure (aim 1). The research builds on well-established cohorts in San Francisco, which include a study of primary HIV-1 infection that identifies persons who appear to be at high risk for super infection based on available animal research and human case reports. We will also test the hypothesis that super infection in highly exposed couples may remain localized in mucosal tissues or limited to small portions of the blood virus population (aim 2). These studies will utilize sensitive virological and serological measurements. Taken together, the proposed research carefully observes massively exposed persons and their partners to determine the frequency of super infection and whether super infection might be limited or contained by host immune responses. Our synergistic approach is designed to provide important novel information that bears directly on HIV-1 epidemiology, protective immunity, and prevention. [unreadable] [unreadable]